5-HT4 receptor (5-HT4R), belonging to serotonin (5-HT) receptor superfamily is positively coupled to adenylate cyclase thereby increasing the cAMP production. 5-HT4Rs are widely expressed throughout the body, but in all species studied so far the highest density of 5-HT4R is observed in the brain regions associated with learning like cortex and hippocampus (Lezoualc'h, F. et. al. The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics, The Humana Press, Chapter 15, 2006, 459-479). Brain microdialysis has shown increased release of acetylcholine in the rat frontal cortex and hippocampus following intracerebroventricular injection of 5-HT4R agonists (Journal of Pharmacology and Experimental Therapeutics, 2001, 296(3), 676-682). Behavioral studies in animal models of learning and memory also support the role of 5-HT4R in cognition.
Interestingly, 5-HT4R also regulates the production of the neurotoxic amyloid β-peptide (Aβ), which is one of the major pathogenetic pathways in Alzheimer's disease (Experimental Neurology, 2007, 203(1), 274-278). Indeed, 5-HT4R agonists can stimulate the non-amyloidogenic pathway leading to the release of the soluble form of the amyloid precursor protein (sAPPα), which in contrast to Aβ, has putative neurotrophic and neuroprotective properties (Journal biological chemistry, 2001, 276(48), 44881-44888). 5-HT4 receptors are, therefore, an exciting potential target for the treatment of Alzheimer's disease symptomatology and pathology (Experimental Neurology, 2007, 205(2), 325-329). Besides this neurodegenerative disorder, 5-HT4R has been described as having mood modulating properties, and these features might be exploited for the treatment of depression (Neuron, 2007, 55(5), 712-725). Thus, 5-HT4R agonists are found to have potential for the treatment of dementia related disorders such as alzheimer's disease, schizpherenia, attention deficit hyperactivity disorder, huntington's disease, parkinson's disease and several other psychiatric disorders (Behavioral brain research, 1996, 73(1-2), 249-52; Schizophrenia Bulletin, 2007, 33 (5), 1100-1119 and Neuroscience & Medicine, 2011, 2, 87-92) and pain (Neuroscience, 2011, 174, 224-233).
5-HT4R agonists also have utility in the treatment of gastrointestinal disorders, especially those associated with reduced esophageal, gastric motility disorders, dyspepsia condition, functional dyspepsia, conditions associated with constipation and irritable bowel syndrome (IBS) and esophagitis (Expert Opinion on Investigational Drugs, 2010, 19(6), 765-775).
Patent publications WO9410174, WO9408994, WO2005049608, WO2006090224, WO2011099305, WO2011101774, US20080207690 and US20080269211 disclosed some 5-HT4 receptor compounds. While several 5-HT4 receptor agonistspartial agonists have been disclosed in the literature, no compound, either agonist or partial agonist targeting 5-HT4 receptor is launched in the market until now for treatments of dementia related disorders. Thereofore, there is need and scope to discover new 5-HT4 receptor agonistspartial agonists with novel chemical structures for treatment of dementia related disorders.
Our quest for finding novel and potent ligands as 5-HT4 agonistspartial agonists had resulted in the discovery of quinoline compounds of the formula (I) which are demonstrating very high affinity and agonist activity towards 5-HT4R with other druggable properties like adequate brain penetration, good oral bioavailability, activity in animal models of cognition, ability to increase cortical sAPPα levels in mice brain significantly and decreasing the levels of Aβ1-40 and Aβ1-42 levels in the rat brain. Therefore, it is an object of this invention to provide compounds, which are useful as therapeutic agents in the treatment of disorders that are affected by the 5-HT4 receptor agonists.